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Immunosuppressive agents

What are Immunosuppressive agents?

 Immunosuppressive agents are drugs that suppress the


immune system and reduce the risk of rejection of foreign
bodies such as transplant organs. Different classes of
immunosuppressive agents have different mechanism of
action. Now immunosuppressive agents are used as cancer
chemotherapy, in autoimmune diseases such as rheumatoid
arthritis and to treat severe allergy. As immunosuppressive
agents lower the immunity there is increased risk of
infection.
 Simplified diagram illustrating the points of action of
immunosuppressive drugs. Corticosteroids inhibit
production of interleukin-1. Macrolides (ie, cyclosporine,
tacrolimus, sirolimus) inhibit production of or use of
interleukin-2, thus inhibiting stimulation of a clone of
cytotoxic T lymphocytes directed against specific human
lymphocyte antigen types. Antimetabolites (ie,
mycophenolate mofetil, azathioprine) inhibit purine
production, thus impairing cell proliferation. Antibodies
impair normal function of cell surface markers, thus
inhibiting stimulation of T-lymphocyte clones directed against
foreign antigens.
Types of Immunosuppressive agents
 calcineurin inhibitors
 interleukin inhibitors
 other immunosuppressants
 selective immunosuppressants
 TNF alfa inhibitors
What are Calcineurin inhibitors?
 Calcineurin inhibitors are medicines which inhibit the action
of calcineurin. Calcineurin is an enzyme that activates T-cells
of the immune system. T-cells (also called T-lymphocytes) are
a type of white blood cell that play a key role in cell-
mediated immunity. Because calcineurin inhibitors suppress
the immune system they are known as immunosuppressants.
 Topical calcineurin inhibitors (pimecrolimus, tacrolimus)
may be used to treat inflammatory skin conditions such as
atopic dermatitis when other treatments have failed. Oral
and injectable calcineurin inhibitors (cyclosporine,
tacrolimus) are used for both the induction and maintenance
of postoperative immunosuppression.
What are Interleukin inhibitors ?
 Interleukin inhibitors are immunosuppressive agents which
inhibit the action of interleukins. Interleukins are a group of
cytokines which are synthesized by lymphocytes, monocytes,
macrophages, and certain other cells. They function
especially in regulation of the immune system.
 Drug name :
Rilonacept; anakinra; -umab (e.g dupilimab, ustekinumab,
secukinumab, etc) ; -zumab (e.g tocilizumab, ixekizumab,
etc)
What are TNF alfa inhibitors?
 TNF-alfa (alpha) inhibitors (TNF-alpha) are a group of
medicines that suppress the body's natural response to tumor
necrosis factor (TNF), a protein produced by white blood
cells that is involved in early inflammatory events.
 TNF-alfa inhibitors treat a wide range of inflammatory
conditions such as rheumatoid arthritis (RA), psoriatic
arthritis, juvenile arthritis, Crohn's disease, ulcerative colitis,
ankylosing spondylitis, and psoriasis.
 Drugs name :
Etanercept, infliximab, adalimumab
What are Selective immunosuppressants?
 Selective immunosuppressive agents are drugs that suppress
the immune system due to a selective point of action. They
are used to reduce the risk of rejection in organ transplants,
in autoimmune diseases and can be use as cancer
chemotherapy . As immunosuppressive agents lower the
immunity there is increased risk of infection
 Drugs name :
Sirolimus, mycophenolate mofetil, natalizumab, leflunomide,
fingomolid, dimethyl fumarate
Other immunosuppressants
 Pomalidomide, Methotrexate, azathioprine, omalizumab,
lenalidomide, thalidomide
Tacrolimus
 Tacrolimus is a macrolide antibiotic and is active against helper T cells,
preventing the production of IL-2 via calcineurin inhibition (binds to
tacrolimus-binding protein instead of cyclophilin protein). The
tacrolimus:FKBP12 active complex inhibits calcineurin with greater
potency than the corresponding cyclosporine complex. This agent is
used for maintenance immunosuppression and for rescue therapy in
patients with refractory rejection under cyclosporine-based therapy.
 Adverse effects are similar to those of cyclosporine but with a lower
incidence of hypertension, hyperlipidemia, skin changes, hirsutism, and
gum hyperplasia and a higher incidence of new-onset diabetes mellitus
after transplantation (NODAT) and neurotoxicity. Although tacrolimus
causes less cosmetic effects than cyclosporine, it can cause reversible
alopecia.
Mammalian target of rapamycin (mTOR) inhibitors
 Sirolimus, also called rapamycin, is a macrolide product of a soil fungus found on Easter
Island. This agent is used for maintenance immunosuppression and chronic rejection.
Everolimus is a rapamycin analog with a similar mechanism of action and adverse effect
profile.
 The mode of action of sirolimus is to bind the cytosolic protein-FKBP12 in a way
similar to tacrolimus. Unlike the tacrolimus-FKBP12 complex, which inhibits
calcineurin, the sirolimus-FKBP12 complex inhibits the mTOR pathway by directly
binding the mTOR Complex1 (mTORC1). This complex inhibits signal 3 by stopping
translation of the RNA and preventing the progression from G1 phase to the S phase of
DNA synthesis. It also inhibits IL-2– and IL–4-dependent proliferation of T and B cells.
 Similarly, sirolimus inhibits proliferation of nonimmune cells and the pathways that
could be involved in oncogenesis. The antiproliferative effects of sirolimus may have a
role in treating cancer.
 Adverse effects associated with mTOR inhibitors are hyperlipidemia,
thrombocytopenia, anemia, pneumonitis, oral ulcers, and diarrhea. Low testosterone
levels may cause infertility. These agents can also cause poor wound healing and
dehiscence formation of lymphoceles. When used combination with calcineurin
inhibitors, sirolimus potentiates calcineurin nephrotoxicity. Sirolimus is associated with
worsening of proteinuria. It may also cause delayed recovery from acute tubular
necrosis.
Mycophenolate acid
Mycophenolate acid inhibits the enzyme inosine
monophosphate dehydrogenase (IMDH; required for
guanosine synthesis) and impairs B- and T-cell proliferation,
sparing other rapidly dividing cells (because of the presence
of guanosine salvage pathways in other cells). This agent is
used for maintenance immunosuppression and chronic
rejection.
 Adverse effects include nausea, vomiting, diarrhea,
leukopenia, anemia, and thrombocytopenia.
 MYCOPHENOLATE MOFETIL
 Introduction: Mycophenolate mofetil is a mycophenolic acid prodrug. It was
widely used in the 1970s to treat refractory psoriasis. Mycophenolate mofetil
has more advantages when compared with mycophenolic acid because it has
greater bioavailability, efficiency and tolerability.
 Mechanism of action and pharmacokinetics: Mycophenolate mofetil inhibits
inosine monophosphate dehydrogenase, an enzyme responsible for metabolizing
purines. Since T and B-lymphocytes use this metabolic route, its inhibition
causes suppression of lymphocytes proliferation, of formation of autoantibodies,
of leukocyte recruitment, and of endothelial binding proteins glycosylation.
Due to the selective inhibition of only one enzyme in the synthesis of purines,
this drug is considered more selective when compared with azathioprine, which
affects several cell lineages. This fact makes it possible for mycophenolate
mofetil to be used in patients with deficiency of thiopurine methyltransferase.
Another advantage in relation to azathioprine is that mycophenolate mofetil is
less mutagenic.
 Indications:
 As a steroid sparing treatment46,47: pemphigus vulgaris,
pemphigus foliaceus, bullous pemphigoid, atopic
dermatitis47; Based on our experiences, mycophenolate
mofetil is the best steroid sparing drug to be used in the
treatment of bullous diseases.
 As monotherapy: bullosis (when corticosteroid use is
restricted),48,49 pyoderma gangrenosum.50 Associated with
other drugs: vasculitis, collagenoses.
 Posology: Mycophenolate mofetil therapeutic regimen should be initiated with
gradual dose increases, every 2-4 weeks, to avoid gastrointestinal effects. If
necessary, dose adjustments should be made for nephropatic patients. The
recommended dose is 35-45 mg/kg/day (up to 2g), administered every 12
hours with food. It is available for oral administration in capsules containing
500mg. Therapeutic effects occur within 6 to 8 weeks. Currently, another form
of the drug, sodium mycophenolate, is available. This drug causes fewer adverse
gastrointestinal reactions and is available in capsules containing 360mg
(corresponds to 500mg of mycophenolate mofetil).
 Follow-up: It is done through rigorous physical examination (to investigate
lymphonodomegalia and cutaneous neoplasty) and gynecological examination
every 6 months. Laboratory exams are executed in the following manner:
complete blood count (weekly in the first month; every fifteen days in the
second month, bimonthly in the third month), and serum biochemistry
(monthly in the first two months and every two months thereafter).
Calcineurin inhibitors
 These agents combine with binding proteins to inhibit
calcineurin activity. This works to inhibit IL-2, which is a
critical link in the proliferation of helper T cells. Calcineurin
normally exerts phosphatase activity on the nuclear factor of
activated T cells. This factor then migrates to the nucleus to
start IL-2 transcription. Studies have shown that cyclosporine
and tacrolimus were associated with similar rates of graft
survival, but several studies showed lower rates of rejection
episodes with tacrolimus.
Azathioprine
 2nd immunosuppressant identified
 Pro-drug
 Discovered by Sir Roy Calne (1959)
 Inhibits purine synthesis necessary for the
proliferation of cells
 Site of action-DNA (false nucleotide incorporation
 Side effects
 Carcinogen
 Nausea
 Rash
 AZATHIOPRINE
 Introduction: Azathioprine is a synthetic analogue of purine, derivative
of 6-mercaptopurine (6-MP), developed in the late 1950s.4 After
discovery of its anti-inflammatory and immunosuppressive effects,
Dermatology started using it to treat inflammatory diseases.
 Mechanism of action and pharmacokinetics: The active metabolite of
azathioprine is 6-thioguanine, an analogue of purine, structurally similar
to guanine and adenine. Instead of having hidroxyl or amino groups, it
has a thiol group. Incorporation of 6-thioguanine into DNA and RNA
inhibits purine metabolism and cell division. Other activities of 6-
thioguanine are suppression of T-cell function, suppression of B-cells
antibody production, reduction in the number of epidermal Langerhans
cells, and inhibition of their capacity to present antigens. In other words,
it inhibits cell and humoral immunity and the effective phase of the
immune response.
 Azathioprine has a short half-life of about three hours, but
metabolites remain active for a long time, allowing
administration of the drug every 12 or 24 hours.
Subsequently, it is degraded to nicotinic acid and excreted
when it passes through the kidneys. Despite the fact that
azathioprine is approved by the FDA for non-dermatologic
use (for instance, in renal transplant), dermatologists have
been using this drug for more than 35 years to treat severe
dermatosis, always considering the risk-benefit ratio.
 Azathioprine is available in tablet form for oral administration.
Each scored tablet contains 50 mg Azathioprine USP. It should be
prescribed in the dosage of 1-3 mg/kg/day and taken with food. 8
It can be prescribed in a single dose or be divided into two doses.
The second dose is associated with fewer incidences of nausea and
vomiting.
 Follow-up and dose adjustment: Patients should receive follow-up
care by being submitted to clinical and laboratory examinations
during treatment with azathioprine. In the first month, weekly
complete blood counts are performed. In the second month, they
should be done every fifteen days. After that, they are done every
two months. Renal and hepatic functions are evaluated monthly in
the first two months. From the third month on, they are evaluated
every two months.
 Drug interactions: Several drugs interact with azathioprine,
and the most well known is allopurinol, which is a xanthine
oxidase inhibitor, thus increasing the risk of severe
myelotoxicity. If both drugs need to be used in combination,
the dose of azathioprine should be reduced by 25-30%. In
addition, hematology tests must be performed
frequently.9 Captopril may increase the risk of leukopenia. It
can reduce the effects of warfarin and pancuronium, and
higher doses of these drugs may be needed. Azathioprine can
lower the effectiveness of intrauterine devices, so the patient
needs to use alternative contraceptive methods.
Cyclophosphamide
 Cyclophosphamide is a nitrogen mustard alkylating agent that was synthesized in
1958.24 It is approved by the FDA for the treatment of mycosis fungoides; however,
it is used to treat several dermatologic diseases. Its main characteristics are the fact
that it is not specific to any phase of the cell division cycle; it suppresses B-
lymphocytes more than it does T25 lymphocytes and, among the latter, it affects
more intensely T suppressor cells (CD8) than auxiliary (CD4).
 Mechanism of action and pharmacokinetics: The alkylating agent acts in the
following manner: it crosses the nuclear membrane, binds to DNA and inhibits the
synthesis of guanine, cytosine, and adenine, supplanting capacity of repair, with
consequent cell apoptosis. The drug is extensively distributed in the body, including
passage through the hematoencephalic barrier.26 The oral bioavailability of the drug is
75%, achieving plasma peak levels one hour after administration. Its half-life is of 2
to 10 hours in the body. It is a prodrug: it needs to be metabolized by cytochrome
P450 in the liver to be converted into its active form 4- hydroxycyclophosphamide.
Despite the fact that only 13% of the drug is protein bound, approximately 50% of
its metabolites are bound to proteins. The kidneys are responsible for half of the
excretion of its inactive metabolites. Among them, acrolein is the one responsible for
hemorrhagic cystitis and transitional cell carcinoma of the bladder.
 Indications (as a monotherapy or corticosteroid sparer):
Vasculitis (especially Wegener's granulomatosis); bullosis;
neutrophilic dermatosis; collagenosis; infiltrative diseases,
histiocytosis X. Absolute contraindications: Pregnancy
and/or breastfeeding, hypersensitivity to cyclophosphamide;
bone marrow depression. Relative contraindications:
Hepatopathy, nephropathy
 Posology: The recommended oral dose is 1-5 mg/kg/day, which
can be divided or administered in the morning in a single dose. It
is available in tablet form containing 25 and 50 mg or ampoules of
200mg. It is essential that a great amount of liquid be ingested
before and during administration of the drug to avoid the risks of
hemorrhagic cystitis. To treat dermatologic diseases, the dose is
rarely greater than 2-2.5mg/kg/day. Another important factor is
that dosages greater than 200mg/day carry high risk of
myelosuppression, and this effect is not necessary to achieve the
desired immunosuppression. Cyclophosphamide can also be
administered parenterally, by means of pulse therapy. In this case,
monthly infusions are done until the sixth month. After that,
infusions should be done every three months. The dose is increased
until the third application: 1st infusion with 10mg/kg; 2nd
infusion with 12.5mg/kg, and 3rd infusion with 15 mg/kg.
Methotrexate
 Immunosuppressive effects due to inhibition of
enzyme involved in the metabolism of folic acid
 Anti-inflammatory effects due to interruption of
adenosine
 Relatively rapid onset of action (4-6 weeks)
 Side effects
 Stomatitis
 Oral ulcers
 GI upset
 Methotrexate is a chemical analogue of folic acid capable of
competitively and irreversibly inhibiting the enzyme
dihydrofolate reductase. Therefore, the conversion of
dihydrofolate into tetrahydrofolate does not occur, a
necessary co-factor for the transfer of carbon atoms, essential
to DNA and RNA synthesis.12 It also inhibits, in a partially
reversible way, the enzyme thymidylate synthase, involved in
cell proliferation.
 Another form of cyclophosphamide administration is pulse therapy associated
with dexamethasone.27 This combination regimen is indicated in cases of very
severe pemphigus or those cases refractory to usual therapy. The
cyclophosphamide-dexamethasone pulse therapy regimen would be
implemented with intervals of 21 or 28 days. On the first day sequential
cyclophosphamide-dexamethasone pulses are done. On the second and third
days, only dexamethasone is used. Cyclophosphamide (1000mg or 10-15
mg/kg) is diluted in 500ml of GS5%, infusing it in 3 to 4 hours.
Dexamethasone 100mg (2ml ampoule with 25 mg - 4 ampoules) is diluted in
250 ml of GS5%, infusing it in 3 to 4 hours.
 The main recommendations are to maintain intravenous hydration in the three
days, to administer bromopride 10 mg and/or ondansetron in cases of nausea,
and to evaluate vital signs at short intervals. If the patient is diabetic, a
hemoglucotest should be performed every 6 hours and a regular insulin
regimen should be prescribed. Corticosteroid should be reduced until the
minimum dose. At least six cycles are necessary. These can be maintained for up
to 2 years. If a significant response is obtained after the 6th cycle, cycles every 2
or 3 months should be attempted.
 Follow-up: Clinical evaluation (physical exam, preventive
gynecological examination, and thoracic radiography) every
six months; complete blood count, abnormal elements and
urine sediments (weekly for 2 to 3 months; after that, every
two weeks). After six months, if the patient is stable, they
should be done every three months. Monthly TGO and TGP
should be done in the first three months and after that every
three months. During treatment, drug administration must
be interrupted if the following occur: leukocytes < 4,000
cells/mm3; platelet count < 100.000mm3 or hematuria.
Cyclosporine
 3rd immunosuppressant identified
 Cyclic nonribosomal peptide
 Discovered by Hartmann F. Stahelin (1972)
 Site of action- calcineurin (inhibits phosphatase
activity)
 Side effects
 Interacts with a wide variety of other drugs and
substances
 hyperplasia, convulsions, peptic ulcers, fever,
vomiting, diarrhea, confusion, breathing
difficulties, numbness and tingling, high blood
pressure, kidney and liver dysfunction
 Introduction: The drug belongs to the family of calcineurin
inhibitors and it was initially approved by the FDA in 1983 to
reduce the risk of organ transplant rejection. Later, it was
approved to treat rheumatoid arthritis and psoriasis.
 Mechanism of action and pharmacokinetics: It is a prodrug - it is
inactive until bound to its cytoplasmic receptor, known as
cyclophilin. Inside T cells, the complex cyclosporine-cyclophilin
inhibits the activity of phosphatase calcineurin responsible for the
dephosphorylation of nuclear factors of active T lymphocytes.
Dephosphorylation allows the translocation of the nuclear factor
of active T cells from the cytoplasm to the nucleus, activating T
cells and producing cytosines such as IL-2 and IFNγ. This explains
why T cells are particularly sensitive to the inhibitory effects of
cyclosporine.
 Contrary to other immunosuppressive drugs with cytotoxic
action, cyclosporine does not cause bone marrow
suppression and teratogenic effects.
 Indications: Psoriasis (erythrodermic, arthropathic, pustular,
recalcitrant, "social"); atopic dermatitis,30 suppurative
hydradenitis; Behcet's disease; collagenoses; lichen
planus;31 Sweet's syndrome, alopecia areata;32 pyoderma
gangrenosum.
 Posology: Cyclosporine is available in capsule form (10, 25, 50, and
100mg) and oral solution (100mg/ml). The latter is a good option for
children and should be diluted in orange or apple juice or soft drinks,
immediately before administration. Milk should be avoided.
 The daily dose recommended is between 3-5 mg/kg/day, and it should
be divided into two doses36 taken with food. Therefore, a patient who
wishes to get better faster may use higher doses, whereas those at risk
for drug interactions may use lower doses.
 A few considerations about the use of cyclosporine: the drug should
preferably not be used continuously for more than 8-12 months; use the
drug in the acute stage of dermatosis38, perform rotational therapy with
other drugs; slowly reduce the dose based on clinical improvement to
avoid drug rebound effect (reduce 0.5mg/kg every 15 days), and
perform maintenance with pulse therapy (when the patient reaches the
low dose of 1.5-2mg/kg/day, administer accumulated dose of three days
and do not administer the drug in the next two days).
Etanercept (Enbrel)
 Recombinant DNA drug
 binds TNF (tumor necrosis factor) in the circulation
and in the joint, preventing interaction with cell
surface TNF receptors thereby reducing TNF
activity
 Subcutaneous injection
 Side effects
 Susceptibility to opportunistic infection
 Abatacept
 Inhibits costimulation of T cells
 Interferes with the process of turning T cells on
which activate cells that cause inflammation
and damage
 Delays progression of structural damage
 Side effects
 Back pain
 Cough
 Dizziness
 Headache
 Susceptibility Infection
References
 www.drugs.com
 www.medicine.medscape.com
 https://www.ncbi.nlm.nih.gov/pubmed/22139982 :
[Immunosuppressive drugs - how they work, their side
effects and interactions]
 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3753
725/ : Immunosuppressive Drug Therapy
 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4741
049/ : Immunosuppressive Medications
 https://www.ncbi.nlm.nih.gov/pubmed/20464082 :
[Immunosuppressive agents in Dermatology].
 https://www.ncbi.nlm.nih.gov/pubmed/9589197 :
Immunosuppressive agents in dermatology. An update.